A Novel Small-Molecule Antagonist of the NOD1 Signaling Pathway as a Therapeutic Strategy for Acute Pancreatitis

Abstract Acute pancreatitis (AP) is a sterile inflammatory disease characterized by aberrant zymogen activation, tissue autodigestion, and cross-amplifying inflammatory cascades that complicate targeted therapies. Our single-cell transcriptomics analysis revealed early NOD1 pathway activation in pancreatic acinar and ductal cells in cerulein-induced AP mice, suggesting potential involvement across these cell types. Here, through a scaffold-hopping strategy, we obtained novel-scaffold NOD1 antagonists. Further optimization yielded 32q and its highly water-soluble disodium salt, 32q-2Na. They exhibited low-nanomolar potency against NOD1 with high selectivity. 32q-2Na pharmacologically inhibited NOD1 signaling, significantly reducing serum levels of amylase (AMY), lipase (LIP), MCP-1, and IL-6, and markedly attenuating pancreatic inflammatory responses in cerulein- and FAEE-induced murine models of AP. In conclusion, these findings establish NOD1 as a highly tractable upstream regulatory node for AP intervention.